Some embodiments relate to the use of creatine kinase or fragments thereof which induce analgesia, and also to the use of pharmaceutical compositions including the same. In particular, two novel peptides that include or consist of the amino acid sequence 1-75 and 184-258 derived from the amino acid sequence of creatine kinase exhibit an analgesic activity, thereby proposing them as an interesting substitute for morphine. Some embodiments are directed to treat or prevent pain.
In the following description, the references in brackets ([ ]) refer to the list of references presented at the end of the text.
Creatine kinase (CK, EC 2.7.3.2), also called phosphocreatine kinase or creatine phosphokinase (CPK), is an enzyme expressed by various tissues including the brain and muscles, where it is present in cytoplasmic and mitochondrial form. There are several isoenzymes (present in the form of noncovalent dimers): CK-MM present in muscles, CK-MB found in the myocardial cells, and CK-BB which occurs in the brain. Mitochondrial CK (mtCK) also occurs. This enzyme catalyzes the reversible conversion of creatine to phosphocreatine via the use of adenosine triphosphate (ATP, FIG. 1). This enzyme is essential for the production of ATP from stored phosphocreatine. Phosphocreatine, via ATP, thus constitutes a reservoir of energy that is rapidly usable for the muscles and other organs including the brain. CK (isoforms MM and MB; dimers) is released in the blood during tissue lesions causing cellular lysis (for example in a muscle disorder such as rhabdomyolysis, muscular effort, myocardial infarction, etc.). Assaying isoenzymes in the blood makes it possible to differentiate the origin of the cellular destruction. Thus, increase in blood CK-MB has been used in a blood test for diagnosing myocardial infarction.
In addition to its role in the metabolism of ATP, it has been recently shown that CK forms non covalent complexes of very high affinity with morphine [Patent Application FR 2 971 161] [6]. The functional consequences of this interaction are not yet clearly defined, however results show that the enzymatic activity of CK (production of ATP from phosphocreatine) is inhibited by morphine by almost 18% (FIG. 2).
Taking into account and treatment of pain are essential aspects of improving the quality of life of patients. Pain affects a considerable number of individuals, about 60 million in Europe each year, which represents an annual cost of 1 billion dollars in analgesic drugs for pain relief. The amount spent annually throughout the world on analgesic drugs was evaluated at approximately 42 billion dollars in 2010. Pain is divided up into two categories: acute pain and chronic pain. Acute pain corresponds to rapid and brief pain which is limited over time. Conversely, chronic pain is a persistent pain which can be linked, for example, to hyperalgesia, and which constitutes an enormous disease burden, affecting approximately 20% of adults and 50% of the elderly population.
The treatment of pain is based essentially on the prescription of anti-inflammatory drugs, whether they are nonsteroidal (NSAIDs) or steroidal (corticoids), and of weak or strong opiates. NSAIDs form the therapeutic class most widely prescribed throughout the world, owing to their great efficacy both on inflammation and on pain itself. They are used in all types of inflammatory pain, whether acute or chronic [Bertin and Vergne-Salle, 2007] [1]. When NSAIDs and/or corticoids are not sufficient to relieve inflammatory pain, the prescribing physician combines a non-anti-inflammatory analgesic, for example paracetamol, weak opioids (codeine, tramadol), and, if the pain continues to be resistant to the treatment, strong opioids (morphine, oxycodone, fentanyl) [Gutstein & Akil, 2006] [2].